1,12-dimethyl-6-hydroxy-7-acyl-9-oxo-1,2,3,4,9,10,11,12-cotahydrophenan-threne-1-carboxylic acids and derivatives thereof



' phenyl.

nited States Patent r 2,854,474 Ice Patented Sept. 30, 1958 1,12 DINIETHYL 6 HYDROXY 7 ACYL 9 OX 1,2,3,4,9,10,11,12 OCTAHYDROPHENAN- TNE 1 CARBOXYLIC ACIDS AND DERIV- ATIVES THEREOF Roy H. Bible, Jr., Morton Grove, IlL, assignor to G. D. Searle & Co., Chicago, 111., a corporation of Delaware No Drawing. Application July 19, 1956 Serial No. 598,764

12 Claims. Cl. 260468.5)

The present invention relates to polyhydrophenanthrene compounds, and is specifically concerned with 1,12 dimethyl-6-hydroxy-7 -acy1-9-oxo-1,2,3,4,9,10,11,12- octahydrophenanthrene-l-carboxylic acids and with ethers and esters thereof. The compounds of the present invention can be representedby-the structural formula OR CH3 COR wherein R can represent hydrogen or a lower alkyl radical, R can represent a lower alkyl radical or an aromatic radical containing fewer than 9 carbon atoms, and R" can represent hydrogen or a lower alkyl radical.

The lower alkyl radicals which R, R, and R can represent can be selected from among such radicals as methyl, ethyl, propyl, butyl, amyl, hexyl, heptyl, octyl, and branched-chain isomers thereof.

When the term R in the foregoing structural formula is an aromatic radical containing fewer than 9 carbon atoms, it can represent an aromatic hydrocarbon radical such as phenyl, methylphenyl, dimethylphenyl or ethyl- It can also represent an aromatic halohydrocarbon radical such as chlorophenyl, bromophenyl, iodophenyl, dichlorophenyl, tribromophenyl, and similarly halogenated methylphenyl, dimethylphenyl, and ethylphenyl radicals. In addition, it can represent an alkoxyhydrocarbon radical such as methoxyphenyl, dimethoxyphenyl, ethoxyphenyl, and methoxymethylphenyl, a common feature of the foregoing aromatic radicals being that they contain fewer than 9 carbon atoms.

This is a continuation-in-part of my copending application Serial No. 347,165, filed April 6, 1953, now U. S.

mula

O-(lower)alky1 0113 l H O COO-(lower)a1ky1 is subjected to an aluminum chloride-catalyzed condensation with an acyl chloride of the structural formula '2 R being defined as hereinbefore, and the resulting 7-acyl substitution product is separated and oxidized in a reaction medium comprising chromium trioxide and aqueous acetic acid, whereby the 9-oxo derivative results. I

Upon treatment of the resulting alkyl ester of 1,12- dimethyl-6-a1koxy-7-acy1-9-oxo -'1,2,3,4,9,10,l1,12 octahydrophenanthrene-l-carboxylic acid with pyridine hydrochloride as set forth in detail hereinafter, there occurs cleavage of the ether and ester groups with the formation of a 1,1Z-dimethyl-6-hydroxy-7-acyl-9-oxo-1,2,3,4,9,10, 11,'lZ-octahydrophenanthrene-l-carboxylic acid. Selective hydrolysis of the 6-alkoxy or the 'l-alkoxycarbonyl group can also be achieved. By treatment in a refluxing solution of hydrobromic acid and acetic acid the ether function is preferentially hydrolyzed; whereas treatment with hot, concentrated sulfuric acid followed by dilution with water causes preferential hydrolysis of the ester function.

The compounds of the present invention have valuable pharmacological properties. Specifically, they are potent anti-hypertensive agents, and are consequently useful in the treatment of states of elevated blood pressure.

The alkyl esters of 1,1Z-dimethyl-6-alkoxy-7-aroyl- 1,2,3,4,9,10,11,12-octahydrophenanthrene 1 carboxylic acid, wherein the aroyl group is a benzoyl radical or substituted benzoyl radical as disclosed here in as intermediates in the manufacture of the claimed 9-oxo ,compositions, also have useful biological properties. They are anti-inflammatory agents, efiective in the treatment of inflammation of the iris. They also have anti-bacterial properties, exhibited, for example, against B. subtilis and E. coli.

This invention will appear more fully from the examples which follow. These examples are set forth by Way of illustration only and it will be understood that .the invention is. not to be construed as limited in spirit or in scope by the details contained therein, as many .modifications in materials and methods will be apparent from this disclosure to those skilled in the art. 'In these examples temperatures are given in degrees centigrade C.) and quantities ofmaterials in parts by weight.

Example 1 To a solution of 5 parts of methyl O-methyl-7-acety1- podocarpate in 53 parts of acetic acid maintained at about 5-10" C. there is gradually added a solution of 3.16 parts of chromium trioxide in 1.5 parts .ofwater and 6 parts of acetic acid. Stirring is continued for 30 minutes after the addition is complete, and .the mixture is then allowed to stand at about 5-10 C. for 48 hours and at about 25 C. for 72 hours. Unreacted chromium trioxide is decomposed by the addition of ethanol, and the mixture is :diluted with several times its volume of water. When separation of the insoluble product is complete, it is collected on a filter and washed. Recrystallization from a mixture of methanol and ethyl acetate afiords the purified methyl ester of 1,12-dimethyl-6- methoxy 7 acetyl 9-oxo-1,2,3,4,9,10,11,12-octahydrophenanthrene-l-carboxylic acid melting ,at about 248- 249.5 C. This compound has the structural formula OCH; CH3 I Example 2 A solution of 2 parts of the methyl ester of 1,12-

dimethyl 6 methoxy 7 acetyl 9 oxo 1,2,3,4,9,

OH CH: l

COCH:

C O OH Example 3 To a stirred mixture of 83 parts of methyl O-methylpodocarpate and 450 parts of chlorobenzene, maintained at about 10-15 C., there is added a total of 75 parts of aluminum chloride in several portions over a 10 L minute period. There is then added over a 30. minute period a solution of 42 parts of benzoyl chloride in 40 parts of chlorobenzene. The mixture is allowed to warm to room temperature gradually and is then allowed to stand at about 25 C. for 18 hours, after which it is poured into several times its volume of ice water which has been acidified with hydrochloric acid. The resulting mixture is distilled under reduced pressure until almost all of the chlorobenzene is removed, after which it is extracted with several portions of ether. The combined ether extract is washed with 10% hydrochloric acid, with water, with 10% sodium hydroxide solution, and finally with several portions of water, after which it is concentrated to dryness. By several crystallizations of the non-volatile residue from aqueous acetic acid and then from aqueous methanol there is obtained the methyl ester of 1,12-dimethyl-6-methoxy- 7 benzoyl 1,2,3,4,9,10,11,l2 octahydrophenanthrenel-carboxylic acid which melts at about 114-119 C. and has the structural formula OCH:

C 0 0 CH1 Example 4 To a stirred solution of 10 parts of the methyl ester of 1,12 dimethyl 6 mcthoxy 7 benzoyl 1,2,3,4,9, 10,11,12-octahydrophenanthrene-l-carboxylic acid in 105 parts of acetic acid maintained at about 10-20" C.,' there is gradually added a solution of 5.2 parts of chromium trioxide in 4 parts of water and 12 parts of acetic acid. The mixture is stirred for an additional hour at 10-20 C. and then allowed to stand at about 25 C. for 72 hours. The mixture is poured into 500 parts of water, with stirring, and the insoluble product is collected on a filter and washed with water. Purifiseveral times its volume of acidified ice water.

4 cation by recrystallization from aqueous methanol yields the methyl ester of 1,1Z-dimethyl-6-methoxy-7-benzoyl- 9 oxo 1,2,3,4,9,10,11,12 octahydrophenanthrene 1- carboxylic acid. This compound melts at about 174- 176 C. and has the structural formula CHI COOCH:

Example 5 By the procedure of Example 3, with the substitution of 50 parts of o-ethylbenzoyl chloride for the benzoyl chloride, there is obtained the methyl ester of 1,12- dimethyl 6 methoxy 7 (o ethylbenzoyl) 1,2,3,4, 9,10,11,12 octahydrophenanthrene 1 carboxylic acid.

Upon oxidation of 10 parts of this compound with chromium trioxide in aqueous acetic acid according to the procedure of Example 4, there results the methyl ester of 1,12 dimethyl-6-methoxy-7-(o-ethylbenzoyl)-9- oxo 1,2,3,4,9,10,11,l2 octahydrophenanthrene 1- carboxylic acid of the structural formula HaC COOC a Example 6 To a stirred mixture of 30 parts of methyl O-methylpodocarpate in parts of chlorobenzene maintained at about 10-15" C. There is added 27 parts of aluminum chloride over a 10 minute period followed by a solution of 35 parts of p-chlorobenzoyl chloride and 15 parts of chlorobenzene over a 30 minute period. The mixture is allowed gradually to warm to room temperature and then to stand for about 18 hours, after which it is poured into Most of the chlorobenzene is removed by distillation under reduced pressure, and the remaining mixture is extracted with several portions of ether. The combined ethereal extract is washed with 10% hydrochloric acid, with water, with 10% sodium hydroxide solution, and with several portions of water, and is then concentrated to dryness. By two crystallizations of the nonvolatile residue from mixtures of ethyl acetate and petroleum ether there is obtained the methyl ester of 1,12-dimethyl-6-methoxy- 7 (p chlorobenzoyl) l,2,3,4,9,10,1l,12 octahydrophenanthrene-l-carboxylic acid which melts at about 144 C. and has the structural formula OCH:

OH: I

Example 7 To a solution of parts of the methyl ester of 1,12- dimethyl 6 methoxy 7 (p chlorobenzoyl) 1,2,3, 4,9,10,1l,12-octahydrophenanthrene-1-carboxylic acid in 105 parts of acetic acid maintained at about C. there is gradually added a solution of 2.2 parts of chromium trioxide in 1 part of water and 4 parts of acetic acid. The mixture is then allowed slowly to warm to room temperature and is maintained at this temperature for about 24 hours, after which it is poured into several times its volume of water. recrystallized from mixtures of chloroform and methanol to afford the purified methyl ester of 1,12-dimethyl-6- methoxy 7 (p chlorobenzoyl) 9 oxo 1,2,3,4,9,10, 11,12-octahydrophenanthrene-l-carboxylic acid melting at about 262-264 C. It has the structural formula OCH:

CE: I

HBO/\COOCHB Example 8 OCH;

HaO OO 0 CH3 Example 9 To a stirred mixture of 30 parts of methyl O-methylpodocarpate and 110 parts of chlorobenzene maintained at 10-15 C. there is added 27 parts of aluminum chloride over a 10 minute period followed by a solution of 34 parts of o-methoxybenzoyl chloride and parts of chlorobenzene over a 30 minute period. Stirring is continued for 3 hours While the mixture is gradually allowed to Warm to room temperature. It is then maintained at about C. for 18 hours, after which it is poured into several times its volume of acidified ice water. Almost all of the chlorobenzene is removed by distillation under reduced pressure, and the remaining mixture is extracted with several portions of ether. The ethereal extract is washed successively with 10% hydrochloric acid, with water, with 10% sodium hydroxide solution, and with several portions of water, after which it is concentrated to dryness. The residue is crystallized from aqueous methanol to afford the methyl ester of 1,12-dimethyl-6- methoxy 7 (o methoxybenzoyl) 1,2,3,4,9,10,11,12-

The insoluble product is collected and 6 octahydrophenanthrene-l-carboxylic acid melting at about 118-121 C. The structural formula is OOOCH:

OCHa

Example 10 To a solution of 5 parts of the methyl ester of 1,12- dimethyl 6 methoxy 7 (o methoxybenzoyl) 1,2, 3,4,9,l0,11,12 octahydrophenanthrene 1 carboxylic acid in 55 parts of acetic acid maintained at about 10 0. there is gradually added a solution of 2.2 parts of chromium trioxide in 1 part of water and 4 parts of acetic acid. The mixture is allowed to warm slowly to room temperature and is then maintained at about 25 C. for 18 hours, after which it is poured into several times its volume of water. By crystallization of the precipitated product from aqueous methanol there is obtained the methyl ester of 1,12-dimethyl-6-methoxy-7-(o-methoxybenzoyl) 9 oxo 1,2,3,4,9,10,11,12 octahydrophenanthrene-l-carboxylic acid which melts at about 175--176 C. and has the structural formula OOHa CH3 I .3GHz

C 00 CH 3 Example 11 OOHa 1130 C O 0 CH5 Example 12 Diethyl sulfate (46.2 parts) is added, with stirring, to a solution of 27.4 parts of podocarpic acid and 12.8 parts of sodium hydroxide in 50% aqueous ethanol, and the resulting mixture is boiled for 5 minutes, and allowed to cool. The precipitated ethyl O-ethylpodocarpate is collected on a filter and Washed with dilute sodium carbonate solution and with Water. The ethylO-ethylpodocarpate 7 is dried thoroughly in a vacuum desiccator. A solution prepared from 19.7 parts of this product and 13.5 parts of butyryl chloride in 250 parts of nitrobenzene is cooled to C. and treated with 16.2 parts of aluminum chloride added in several portions over a period of 1 hour. The mixture is stirred at 0 C. for an additional 3 hours, and then allowed to stand at 0-5 C. for 100 hours and finally at about 20 C. for hours. The mixture is then stirred with ice and dilute hydrochloric acid. The nitrobenzene phase is separated, washed with several portions of water and distilled with steam until the organic solvent is removed. The remaining aqueous suspension is extracted with ethyl acetate, and the ethyl acetate solution is washed with water and concentrated to dryness under reduced pressure. The non-volatile residue consists substantially of ethyl O-ethyl-7-butyrylpodocarpate. A solution of 5 parts of this crude product in 105 parts of acetic acid maintained at about 5-10" C. is treated by the gradual addition of a solution of 3.16 parts of chromium trioxide in 1.5 parts of water and 6 parts of acetic acid. The mixture is allowed gradually to warm to room temperature and then is maintained at about 20-25 C. for 24 hours. The mixture is then poured into several times its volume of water, and the precipitated product is col- OCIHI OH: I

COCHsCHsCH:

Example 13 A solution of 1 part of the methyl ester of 1,12-dimethyl-6-methoxy-7-acetyl-9-oxo-1,2,3,4,9,10,11,12 octahydrophenanthrene-l-carboxylic acid in 16 parts of concentrated sulfuric acid is heated at about 80 C. for 4 minutes, during which time there occurs an evolution of sulfur dioxide. The hot solution is poured with stirring, into several times its volume of water and the precipitated solid is collected on a filter and then extracted with 5% sodium hydroxide solution. This basic extract is filtered, and the filtrate is poured into hot hydrochloric acid, whereby there is obtained a precipitate of 1,12-dimethyl- 6-methoxy-7-acetyl-9-oxo l,2,3,4,9,10,1l,12 octahydrophenanthrene-l-carboxylic acid. Upon crystallization from a mixture of water and methanol this compound melts at about 195196.5 C. It has the structural formula O OH:

COOH

8 What is claimed is: 1. A compound of the structural formula OR CHI COR H10 0 O O R" wherein R is a member of the group consisting of hydrogen and lower alkyl radicals; R is a member of the group consisting of lower alkyl radicals, monocyclic aromatic hydrocarbon radicals containing fewer than 9 carbon atoms, monocyclic aromatic halohydrocarbon radicals containing fewer than 9 carbon atoms, and monocyclic aromatic alkoxyhydrocarbon radicals containing fewer than 9 carbon atoms; and R is a member of the group consisting of hydrogen and lower alkyl radicals.

2. A compound of the structural formula O-(lower alk 1 CE; I y

C O-(lower)alkyl H'C COO-(lower)alkyl 3'. Lower alkyl ester of 1,12-dimethyl-6-methoxy-7- acetyl9-oxol,2,3,4,9,l0,11,12 octahydrophenanthrenel-carboxylic acid.

4. Methyl ester of 1,1Z-dimethyl-6-methoxy-7-acetyl- 9-oxo-1,2,3,4,9,10,11,12-octahydrophenanthrene 1 carboxylic acid.

5. A compound of the structural formula H10 00 OH 6. 1,12 dimethyl 6 hydroxy 7 acetyl 9 oxo- 1,2,3,4,9,10,11,l2-octahydrophenanthrene 1 carboxylic acid.

'7. A compound of the structural formula 0- 1 cm C NN CO-Y H10 6 O O-(lower)alkyl 9 10' wherein Y is a monocyclic aromatic hydrocarbon radical 11. A compound of the structural formula containing fewer than 9 carbon atoms. muownm] 8. Methyl ester of 1,12-dimethyl-6-methoxy-7-benzoyl- CH3 9-oxo-1,2,3,4,9,10,11,12-octahydrophenanthrene 1 carcotalkoxyaryl boxylic acid. 5

9. A compound of the structural formula 0-! alk l CH3 I (ower) y \J=O CO-haloaryl H30 CO0-(1ower)alkyl wherein the alkoxyaryl radical is a monocyclic aromatic alkoxyhydrocarbon radical containing fewer than 9 car- 16 bon atoms. -0 12. Methyl ester of 1,12-dimethyl-6-methoxy-7-(omethoxybenzoyl)-9-oxo 1,2,3,4,9,10,11,12, octahydro- H30 C 0 O-(10wer) 1kyl phenanthrene-l-carboxylic acid.

h th h 1 1 r I y I, at References Cited in the file of this patent w erem e a oary a ma 1s a mon c1c orna 1e 20 halohydrocarbon radical containing fewer than 9 carbon UNITED STATES PATENTS atoms. 2,750,373 Bible June 12, 1956 10. Methyl ester of. 1,12-dimethyl-6-methoxy-7-(p- 2,750,407 Ritchie June 12, 1956 chlorobenzoyl) 9 0x0 1,2,3,4,9,10,11,12 octahydro- 2,759,014 Bible Aug. 14, 1956 phenanthrene-l-carboxylic acid. 25 2,767,162 Picha Oct. 16, 1956 

1. A COMPOUND OF THE STRUCTURAL FORMULA 